Currently available therapeutics for follicular lymphoma (FL) have limited curative potential and significant toxicities, particularly for the older FL patient population. Novel treatment modalities, such as immunotherapy, that can combine enhanced anti-tumor efficacy with diminished toxicities through targeting of malignant B-cells of FL are needed. The studies proposed here will build on the advances made in FL immunotherapy through antibody-based therapeutics by developing complimentary cellular immunotherapy-based approaches for this disease. We have made significant progress in developing the methodologies for isolating and expanding genetically-modified T-cells that express a CD19-specific chimeric immunoreceptor and display potent and specific anti-tumor effector functioning against CD19 + lymphomas. Moreover, the City of Hope has established platforms for manufacturing clinical-grade genetically-modified ex vivo-expanded T-cell products under FDA-authorized IND's. A pilot Phase I clinical trial is proposed to treat, for the first time, FL patients with refractory/progressive disease with autologous ex vivo-expanded CD19-specific T-cell lines (Aim 1). In addition to answering questions of feasibility, safety, and anti-tumor responses, this trial will study the in vivo persistence, lymph node homing, and immunogenicity of these cell products. The magnitude and duration of in vivo persistence of adoptivelytransferred CD19-specific T-cells will likely be important parameters for clinical efficacy. While we will study the impact of pre-adoptive therapy lymphodepletion and exogenous IL-2 administration on promoting persistence in the context of our pilot study, Aim 2 of this proposal will focus on pre-clinical development of strategies to selectively express the anti-CD19 immunoreceptor in T-cells having desired anti-viral specificity through their endogenous TCRs. Ultimately we hypothesize that such bi-specific T-cells will be amenable to in vivo expansion through vaccination with viral antigen. Aim 3 will focus on promoting the survival and recycling of CD19-specific T-cells in the lymphoma microenvironment by their co-expression of CD28 for coordinated delivery of activation and co-stimulation signals by tumor cells of FL. We anticipate that insights gained from the pilot clinical trial and proposed pre-clinical studies will facilitate the implementation of second-generation adoptive immunotherapy protocols for FL with applications to other B-lineage lymphomas